Cardiovascular diseases related to abnormal lipid metabolism are very frequent in industrialised countries. In Italy, for instance, they account for more than 40% of the overall mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortalità in Italia nell'anno 1989. Rapporto ISTISAN 1992/22). Our knowledge of the relationships between cholesterol and coronary heart disease stem from epidemiological studies conducted over the past few years. The conclusions reached in these studies indicate that the development of severe coronary atherosclerosis and coronary heart disease are closely correlated with serum cholesterol levels (McGill H. C. Jr. et al.: The International Atherosclerosis Project. Lab. Invest. 18: 463-653, 1968; Keys A.: Seven Countries: Death and Coronary Heart Disease. Harvard University Press, Cambridge, 1980).
Correction of eating habits through suitable diet is invariably the first measure adopted in cases of hyperlipidaemia. Satisfactory results are not always achieved, however, owing to widespread intolerance of strict dietary discipline, to the severity of the hypercholesterolaemia, or to genetic-type resistance.
To achieve the desired results in these patients, i.e. normalisation of blood levels of triglycerides and cholesterol, pharmacological treatment has to be resorted to. Hypolipaemic drugs fall into two categories: those which above all reduce cholesterol and those which mainly reduce triglycerides.
The former group of drugs includes the statins, probucol and resins, while the latter group includes the fibrates, nicotinic acid and fatty acids belonging to the omega-3 series.
The statins (lovastatin, simvastatin, provastatin, fluvastatin, and the like) are inhibitors of hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. By inhibiting this enzyme, they reduce the hepatic synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction of intracellular cholesterol the liver cell produces several receptors for LDL and VLDL lipoproteins, which are thus removed from the bloodstream.
The statins are drugs which are better tolerated than the other anticholesterolaemic agents, but are not without drawbacks, the side effects most commonly induced by these drugs being gastrointestinal disorders, skin rashes and headache.
It has been reported that though the statins lead to a reduction in the number of deaths due to coronary heart disease, an increase has been observed, in treated patients, of deaths caused by other events such as tumours or trauma (Davey-Smith G., Song F., Sheldon T. A.: Cholesterol lowering and mortality: the importance of considering initial level at risk. BMJ, 1993; 306: 1367-1373; Ravnshov U.: Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992; 305: 15-19). The results of experiments in animals and human subjects have suggested that, to reduce cholesterol levels, pharmacological treatment with statins should be given only to patients at high risk for coronary disease in the short term (JAMA, 1996; 275: 55-60).
Red yeast rice is the product of yeast (Monascus purpureus) grown on rice, and is served as a dietary staple in some Asian countries. It contains several compounds collectively known as monacolins, substances known to inhibit cholesterol synthesis. One of these, “monacolin K,” is a potent inhibitor of HMG-CoA reductase.
In American Journal of Clinical Nutrition, Vol. 69, No. 2, 231-236, February 1999 it is described the cholesterol-lowering effects of red-yeast-rice supplementation.
The omega-3 fatty acids are known for their triglyceride-lowering effects and for their effects in raising the levels of high-density lipoproteins (HDL).
In BMJ. 2006 April 1; 332(7544): 752-760 it is described the use of omega 3 fatty acids for treating cardiovascular diseases.
The policosanols are long-chain aliphatic alcohols. Examples of policosanols are triacontanol, hexacosanol, hexacontanol, ecocontanol, tetracosanol, dotriacontanol, and tetracontanol. The policosonol can be present as such or in the form of extract from natural products that contain it, e.g. wheat or rice germs, the waxy cuticle of sugar cane, or Ginkgo biloba leaves. Policosanols are widely used in the medical and nutritional field.
In Nutr Rev. 2003 November; 61(11):376-83 it is described the use of policosonol for treating cardiovascular diseases.
Resveratrol (trans-3,4′,5-trihydroxystilbene) is a polyphenol molecule found in many plant species including grapes and others.
In Free Radic Res. 2000 July; 33(1):105-14 it is described the use of Resveratrol for the inhibition of lipid peroxidation.
Coenzyme Q10 is now so well known in its human use that it requires no particular explanation and the substance is available on the market. Experts in the sector can refer to the patent documents filed by the present applicant, where this substance is amply described.
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group widely used in the medical and nutritional field. Several forms of the vitamin are known, but pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen.
Vitamin B12, also called cobalamin, is a water soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. As the largest and most structurally complicated vitamin, it can be produced industrially only through bacterial fermentation-synthesis.
Also Vitamin B12 is widely used in the medical and nutritional field.
L-carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (fats) for the generation of metabolic energy.
In U.S. Pat. No. 4,255,449 it is reported that L-carnitine is useful for increasing the HDL cholesterol and for treating diseases liked to high cholesterol level.
In WO04091602 9 it is reported that L-carnitine is useful the treatment of cardiovascular diseases.
While there are other publications available in which is shown that the compounds of the invention are useful for prophylaxis and/or treatment of hypertriglyceridemia and hypercholesterolemia and related disease states, none of them mention nor suggest about the unexpected synergistic effect shown by the composition of the invention.